Venous thromboembolism (VTE) is a multifactorial disease. Because low-frequency variants and rare mutations have been found to predispose carriers toward VTE, there is a need for variant discovery in clinical settings. Therefore, we used a whole-exome approach for a young VTE patient with a positive family history. We identified in the proband and his affected mother a rare, functional missense variant of prothrombin, p.Arg541Trp, which contributes to the clinical picture of VTE.